Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression

Philipp Du Bois, Cristina Pablo Tortola, Doerte Lodka, Melanie Kny, Franziska Schmidt, Kunhua Song, Sibylle Schmidt, Rhonda Bassel-Duby, Eric N. Olson, Jens Fielitz

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

Original languageEnglish (US)
Pages (from-to)424-436
Number of pages13
JournalCirculation Research
Volume117
Issue number5
DOIs
StatePublished - Aug 14 2015

Fingerprint

Activating Transcription Factors
Muscular Atrophy
Angiotensin II
Fingers
Skeletal Muscle
Transcription Factors
Muscles
Histone Deacetylases
Protein Kinases
Heart Failure
E-Box Elements
Cachexia
Ubiquitin-Protein Ligases
Cell Nucleus Active Transport
Skeletal Muscle Fibers
Hydrolases
Renin-Angiotensin System
Small Interfering RNA
Atrophy
Complementary DNA

Keywords

  • angiotensin II
  • gene expression regulation
  • heart failure
  • histone deacetylase 5
  • muscle RING-finger-1
  • protein kinase D
  • transcription factor EB

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Du Bois, P., Tortola, C. P., Lodka, D., Kny, M., Schmidt, F., Song, K., ... Fielitz, J. (2015). Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression. Circulation Research, 117(5), 424-436. https://doi.org/10.1161/CIRCRESAHA.114.305393

Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression. / Du Bois, Philipp; Tortola, Cristina Pablo; Lodka, Doerte; Kny, Melanie; Schmidt, Franziska; Song, Kunhua; Schmidt, Sibylle; Bassel-Duby, Rhonda; Olson, Eric N.; Fielitz, Jens.

In: Circulation Research, Vol. 117, No. 5, 14.08.2015, p. 424-436.

Research output: Contribution to journalArticle

Du Bois, P, Tortola, CP, Lodka, D, Kny, M, Schmidt, F, Song, K, Schmidt, S, Bassel-Duby, R, Olson, EN & Fielitz, J 2015, 'Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression', Circulation Research, vol. 117, no. 5, pp. 424-436. https://doi.org/10.1161/CIRCRESAHA.114.305393
Du Bois, Philipp ; Tortola, Cristina Pablo ; Lodka, Doerte ; Kny, Melanie ; Schmidt, Franziska ; Song, Kunhua ; Schmidt, Sibylle ; Bassel-Duby, Rhonda ; Olson, Eric N. ; Fielitz, Jens. / Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression. In: Circulation Research. 2015 ; Vol. 117, No. 5. pp. 424-436.
@article{27e047bce3a541d7aaeff549ec8dd621,
title = "Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression",
abstract = "Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.",
keywords = "angiotensin II, gene expression regulation, heart failure, histone deacetylase 5, muscle RING-finger-1, protein kinase D, transcription factor EB",
author = "{Du Bois}, Philipp and Tortola, {Cristina Pablo} and Doerte Lodka and Melanie Kny and Franziska Schmidt and Kunhua Song and Sibylle Schmidt and Rhonda Bassel-Duby and Olson, {Eric N.} and Jens Fielitz",
year = "2015",
month = "8",
day = "14",
doi = "10.1161/CIRCRESAHA.114.305393",
language = "English (US)",
volume = "117",
pages = "424--436",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression

AU - Du Bois, Philipp

AU - Tortola, Cristina Pablo

AU - Lodka, Doerte

AU - Kny, Melanie

AU - Schmidt, Franziska

AU - Song, Kunhua

AU - Schmidt, Sibylle

AU - Bassel-Duby, Rhonda

AU - Olson, Eric N.

AU - Fielitz, Jens

PY - 2015/8/14

Y1 - 2015/8/14

N2 - Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

AB - Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

KW - angiotensin II

KW - gene expression regulation

KW - heart failure

KW - histone deacetylase 5

KW - muscle RING-finger-1

KW - protein kinase D

KW - transcription factor EB

UR - http://www.scopus.com/inward/record.url?scp=84939533247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939533247&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.114.305393

DO - 10.1161/CIRCRESAHA.114.305393

M3 - Article

C2 - 26137861

AN - SCOPUS:84939533247

VL - 117

SP - 424

EP - 436

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 5

ER -